Local anaesthetically active pharmaceutical preparation and method of preparing the sme



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Patented May 25, 1937 2,081,712 Milt/AL ANAESTHE'MCALKJY ACTIVE PEAR= MACEUTICAL PREPARA'H'KQN AND hmm= OF PREPARING THEE Slam No firawinz.

Serial No. 41,025. In Gen (cl. sec-roe) higher alkylene residues can take their place as 12 Claims.

It has already been known for a long time that the water soluble salts of diethylaminoethenyl p-amino-benzoates are anaesthetically active. The chlorhydrate of the diethylaminoethenyl p-amino-benzoate is generally known in medicine by the trade name "novocaine" and is used in order to produce local anaesthesia instead of cocaine formerly exclusively applied. By modification of the aminoalcohol esterlfied with p-amino-benzoic acid and by the introduction of substituents into the amino group of the p-amino-benzoic acid and also by introducing substituents into the benzene nucleus, compounds have been prepared, closely related to novocaine, but more powerful as local anaesthetics than novocaine itself.

By replacing the amino group in p-position by an alkoxyl-group the present invention enters a new way. Using such an alkoxyl-group that contains 3-6 carbon atoms, products are obtained the water soluble salts of which are considerably more powerful local anaesthetics than novocaine. The new products are as active as the most powerful of the compounds mentioned above, but essentially easier to produce. Furthermore the new preparations are distinguished by the rather unexpected combination of high emciency and remarkably low toxicity.

The new local anaesthetlcally active preparations are the water soluble salts of allroxy-diallrylene-amino p-allroxy-benzoates of the general formula: a

R! p-ROCdhCOOWN ii ii Ac where R is an allryi residue with 3-6 carbon atoms, R is an allsylene residue, preferably with. 2. or 3 carbon atoms. R and R are two equal or different allzyl residues oi any number of carhon atoms and. he is an acid radical forming a water soluble salt with the'ester of the amino alcohol.

It will be noted that in the compounds identified by the general formula given above, the benzene nucleus has no substitucnts in the ortho and the meta'positions relatively to the carhoxyl group, this being indicated by the part Cal-l4 of said formula.

R cannot only be a saturated alkyl residue, such as the propyl-, butyl" or arnyl-residue, but also an unsaturated residue, as for example the allyl-group. Furthermore saturated or unsaturated cycloaliphatic residues such as the cyclohexyl-group and the cyclohexenyl-group are to be taken into consideration.

R may be, as already mentioned, preferably the alkylene-residues with 2-3 carbon atoms, i. e. the ethyleneand the propylene-group. But

Carl Rohmann, Jena, Germany Application September lid,

ny Jr W, 1934 well in certain cases. R and R will be chosen to be equal in most cases, since the dialkyl amines with 2 equal substituents are easier to produce than the dialkylamines with unequal substituents. For R and R the lowest alkyl radicals such as the methyl group as well as the higher alkyl radicals such as the ethyland the propylgroup are available. Finally carbon chains possessing two free valencies can take the place of the two alkyl residues,-thus for example a piperldyl group replacing the diallryl amino group when a five membered chain is chosen.

The physiologically mostly indifferent ions such as the chlorine ion are available as the above mentioned acid radical Ac. But organic ions such as the lactic acid ion are appropriate as well, as long as they are able to give a water soluble salt with the amino-alcohol ester.

The production of the new local anaesthetically active preparation is preferably carried out as follows: The phenolic hydroxyl group is etherifled according to, known methods, for example by means of alkyl halogenides, alkyl sulphonates or dialkyl sulphates. The reaction is carried out in alkaline solution to fix the acid produced.

Since the alkyl substituted phenolic hydroxyl has to contain an allryl residue with 3-6 carbon atoms, the corresponding alkyl halogenides, alkyl sulphonates or diallzyl sulphates only are to be taken into consideration.

The resulting p-allsoxy-benzoic acids are transformed into the corresponding acid halogenides, for example by the action oi thionyl chloride. The p-allsoxy benaoyl chlorides obtained then are allowed. to react with allrylene chlorhydrine, for example ethylene chlorhydrine or propylene chlorhydrlne.

Instead the p-alkoxy-benzoyi halogenides the free p allroxy-henzoic acid or esters of the p-allrony-benzoic acid may be used for the reaction with the ailsylene chlorhydrines, but the yields obtainable are not so good as when p-allroxy-benzoyl halogenides are used.

The product obtained by the reaction of the p-alltorryebenaoyl halogenides with the al- .lrylene ehlorohydrines is allowed toreact at an elevated temperature and under pressure with a diallryl amine some other secondary base, as for example piperldine.

The chlorhydrate of the diallryl amine or of some other secondary base is separated from the water insoluble ester of the p-allroxy-benzoic acid by treating the mass with water. The ester is extracted with ether and the ethereal layer reextracted with dilute acid, when the chlorhydrate of the basic ester goes into the aqueous layer.

For further purification the ester can be liberated from the solution by alkalinization and be the the corresponding compounds, which are derived from p-alkoxy-benzoic acids having the phenolic hydroxyl-group substituted by alkyl residues with less than 3 carbon atoms, have very little locally anaesthesizing power. The chlorhydrates oi the diethylamino-ethenyl p-n.butoxy--benzoate and p-isoamyloxy-benzoate respectively are more than a hundred times more active than for example the chlorhydrate of the diethylaminoethenyl p-methoxy-benzoate. v

The physiological experiments for the estimation of the locally anaesthesizing power of the new preparations were carried out as follows:

Frogs are decerebrated with a sharp needle avoiding hemorrhages, suspended on a gallows corresponding to 82% of the theory.

and thehind legs dipped into the solution to be tested. The anaesthesizing solution is exchanged in certain intervals for a 2% acetic acid solution and the frogs reaction to this irritation is observed.

It was found that diethylamine-ethenyl p-n. butoxy-benzoate and the corresponding ester of the p-isoamyloxy-benzoic acid are still active,

when applied in 0.06% solution. Diethylaminoethenyl p-methoxy benzoate had to be applied in solution stronger than 6% in order to produce an effect of local anaesthesia.

The new local anaesthetically' active preparations are in the first place to be used in aqueous solutions, but it is possible, if required, to prepare mucons solutions or to use the preparations as addition to ointments or nose emulsions.

The diethylamino-propenyl p-n.butoxy-benzoate proved to be particularly active as its threshold of activity was smaller than 0.03%.

Example I in a tap funnel with water and a little sodium carbonate solution, the chloroethyl ester extracted with ether, the ethereal solution dried over anhydrous sodium carbonate and evaporated. The residue melts at 32. Yield 27 g.

12 g. of the resulting ester are heated for 30 hours in a sealed tube in an atmosphere "of nitrogen together with 15 g. diethylamine. The product of the reaction is treated with water,

when diethylamine chlorhydrateis dissolved the 'aminated ester separating as an oil. The oil is extracted with ether, the ethereal solution washed with dilute hydrochloric acid, the acidic extract shaken for. an hour with charcoal, filtered, the filtrate made alkaline by the addition of potassium carbonate and the oil re-extracted with ether. The ethereal solution is dried over anhydrous sodium carbonate. By carefully introducing anhydrous HCl-gas under cooling, the

chlorhydrate is precipitated in small crystals. The precipitate is separated by filtration, dried on pieces of porous material and recrystallized from absolute alcohol. The chlorhydrate melts Example II Example III 'g. p-n. butoxy-benzoic acid are treated with thionyl chloride. The acid chloride obtained (3' P. 169 at 18 mm. Hg) is treated with trimethylene chlorhydrine (50 g.). 'y-diethylaminopropenyl p-n.butoxy-benzoate is prepared by heating the resulting ester (107 g.) for 65 hours at with diethylamine (160 g.) The products of the'reaction are worked up as in Example I. The other experimental details correspond closely to those in Example I. The chlorhydrate 'melts at 126-127.

Example IV The acid chloride is prepared from 79 g. p-n.- butoxy-benzoicacid by means of thionyl chloride and boils at 166 at 15 mm. Hg. It is treated with 40 g. ethylene chlorhydrine and the resulting ester is heated for'60 hours at 100 with a solution of 50 g. dimethylamine in 67 g. benzene in order to get the dimethylamino ester. Working up and experimental details as in Example I. The chlorhydrate melts at 127-128".

Example V The acid chloride is prepared from 80 g. p-n.- propoxy-benzoic acid by means of thionyl chloride and treated with 40 g. ethylene chlorhydrine. The resulting ester is heated for 50 hour's at 100 with dipropylamine (100 g.) to give the di-n.propylamino ester. Working up and experimental details as in Example I. The chlorhydrate melts at 119.

Example VI As described in Example III p-n.butoxy-benzoyl chloride is prepared from p-n.butoxy-benzoic acid by means of thionyl chloride. 51.5 g. p-n.- butoxy-benzoyl chloride are diluted with a mixture of benzene-toluene (boiling point 100), 9. solution of 28,3 g. diethylamino-ethanol in g. 'of the same benzene-toluene mixture is slowly added and the mass refluxed for 24 hours. The cool solidified mass is carefully shaken with dilute hydrochloric acid, separated from the benzene-toluene layer, shaken with charcoal and filtered. The base is liberated by the addition of sodium carbonate, extracted with ether and the ethereal solution dried over anhydrous potassium'carbonate. By the careful introduction of anhydrous HCl-gas the base is precipitated as chlorhydrate which is recrystallized from a hot benzene-toluene mixture containing a little alco- Yield approxicosmic henol ester of a p-alkoxy benzoic acid of the following type:

-mooemcoornn where R is an allwl residue with 3-6 carbon atoms, R is an alkylene residue, R and R are two alkyl residues, and Ac is an acid radical forming a water soluble salt with the ester of the amino alcohol.

2. A water soluble salt of a dialkylamino-alkanol ester of a p-allroxy bena'olc acid'of the following type:

R: -a ommcooam a a Ac where R is a saturated alkyl residue with 3-6 carbon atoms, R is an alkylene residue, R and R are two aliryl residues, and Ac is an acid radical forming a water soluble salt with the ester of the amino alcohol.

3. A water solublesalt oi. a dialkylamino alkano! ester of a p-alkoxy benzoic acidoi the following type:

p-R 0CH CO0R N where R isan allryl residue with 3-6 carbon atoms, R. is an ethylene residue, R and R are two alkyl residues, and Ac is an acid radical torming a water soluble salt with the ester of the amino alcohol.

4. A water soluble salt of a dialkylamino alkanol ester of a p-alkoxy benzofc acid oi the i'ollowing type:

s rwooancooan/ where R is an alkyl residue with 3-6 carbon atoms, R is a propylene residue, R and R are two alkyl residues, 'and Ac is an acid radical forming a water soluble salt with the ester 01' the amino alcohol.

5. A water soluble salt of a dialkylamino alkanol ester of a p-alkoxy benzolc acid otthe following type:

-n ocimcoomn H i It where R is a saturated alkyl residue with 3-8 carbon atoms, R is an ethylene residue, R and v R are two alkyl residues, and lie is an acid radical forming a water soluble salt with the ester 01 the amino alcohol.

6. Awater soluble salt of a dialkylamino alkanol ester or a p-alkoxy benzolc acid or the following type:

-n ocimcooam I n L In where n is a saturated .alhl residue with 3- 8 carbon atoms, R? is a propylene residue, R and R are two alkyi residues, and Ac is an acid radical forming a water soluble salt with the ester of the amino alcohol. I

7. As a new compound, the chlorhydrate of pdiethylamino-ethenyl p-n.hutoiry-henzoate.v

8. As a new compound, the chlorhydrate or 'diethylamino-ethenyi p-isoamyloxy-benzoate.

amino alcohol, comprising the alkylation of 52- hydroxy benzoic acid, followed by the'conversion of the p-alkoxy henzolc acid into the corresponding henaoyi halogenide by the action of an inorganic acid halogenlde, followed by the reaction of the henaoyl haioaenide with an allzylene chlorhydrine followed by the heating of the product obtained with an excess of adialiryl amine under pressure and icy conversion 0! the resulting basic ester into a water soluble salt.

11. Method for the preparation of water soluhie compounds of the following type: I

. 0 where R is an alkyl residue with 3-6 carbon atoms, R is an alkyleneresidue, R and R are two alkyl residues, and Ac is an acid radical formhis a water soluble salt with the ester 01' the.

amino alcohol, comprising the alkylation of phydroxy benzoic acid, followed by the conversion of the p-alkoxy benzoic acid into the corresponding benzoyl halogenide by the action of an inorganic acid halogenide followed by the reaction of the resulting benzoyl halogenide with a dialkyl amino alcohol to form the dialkylamino p-alkoxy-b'enzoate and by transformation 01. this ester into a water soluble salt.

7 12. Method for the preparation of water soluble compounds of the following type:

-mocimcoolyn n l n where R is an 'alkyl residue with 3-6 carbon atoms, R is an alkylene residue, R and R are two alkyl residues, and Ac is an acid radical 4 forming a water soluble salt with the ester 01' the amino alcohol, comprising the alk'ylaticn of p-hydroxy benzoic acid, followed by the conversion of the p-alkoxy'benzolc acid into the corresponding benzoyl halogenide by the actiono! an inorganic acid halogenide, then subjecting the henzoyl halosenide to a treatment which will produce a basic ester of the substituted benzoic acid,

- and thereupon converting such ester into a water soluble salt.

cam. 

